Abstract 1844: xCT promotes tumor formation in airway epithelial cells by activation MYC and WNT pathways

Abstract

Abstract INTRODUCTION: Many tumors increase uptake and dependence on nutrients such as glucose, cysteine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Recent studies demonstrated that smoking can induce the expression of xCT (SLC7A11) in normal epithelial cells and cancer cells, suggesting that overexpression of xCT may support lung tumor progression. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Here, we investigated the function of SLC7A11 (xCT), a cystine/glutamate anti-porter, in the pathogenesis of lung cancer. Recently, we found xCT to be strongly overexpressed at the cell surface of lung cancers and began to investigate the mechanisms by which xCT may contribute to lung cancer progression. METHODS: We overexpressed the xCT in mutiple non-tumorgenic cell lines. These cell lines included 16HBE, BEAS2B, HBEC_KTR_P53_C7, and HEK293. We further investigated the role of xCT in cell proliferation, conly formation, and tumor formation in nude mice. Finally, we used RNAseq analysis to indentify the molecular mechanims associated with xCT expression in HEK293 cells. RESULTS: Our results shows that xCT overexpression transformed the normal airway epithelium cell lines (HBEC3_KTR_P53_C7). The overexpression of xCT in HBEC_KTR_P53C7 induced colony formation in soft agar and promoted cell proliferation. In addition, we found overexpression of xCT reprogrammed multiple metabolic pathways such as glycolysis, glutaminolysis, and pentose phosphate pathway. In addition, we found overexpression of xCT could transform non-tumorigenic cell line HBEC_KTR_P53_C7 to tumor-formation cell line. Our RNAseq data indicated that this transformation is enriched in MYC and WNT pathway. CONCLUSION: Our results demonstrate that xCT is highly expressed in a subset of NSCLCs. The induction of xCT in transformed aiway epithelial cells causes tumor formation in nude mice. The mechanism of malignant transformation involves the Warburg effect. Further investigation into the mechanisms of transformation may help in answering fundamental questions pertaining to how glutamate/cystine exchange contributes to lung cancer development and progression and also in establishing xCT as a potential novel therapeutic target in lung cancer. Key words: Non-small cell lung cancer, amino acid transporters, metabolic reprogramming Note: This abstract was not presented at the meeting. Citation Format: Xiangming Ji. xCT promotes tumor formation in airway epithelial cells by activation MYC and WNT pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1844.